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Updated: May 1, 2026

Assessment of Morphine-induced Hyperalgesia and Analgesic Tolerance in Mice Using Thermal and Mechanical Nociceptive Modalities
07:23

Assessment of Morphine-induced Hyperalgesia and Analgesic Tolerance in Mice Using Thermal and Mechanical Nociceptive Modalities

Published on: July 29, 2014

34.8K

Change in functional selectivity of morphine with the development of antinociceptive tolerance

T A Macey1, E N Bobeck, K L Suchland

  • 1Department of Neurological Surgery, Oregon Health & Science University, Portland, OR, USA.

British Journal of Pharmacology
|March 27, 2014
PubMed
Abstract

Insights

Repeated morphine use alters μ-opioid receptor signaling, leading to tolerance. Dynamin-dependent receptor internalization reduces pain relief by affecting ERK activation.

Area of Science:

  • Neuroscience
  • Pharmacology

Background:

  • Opioids are effective analgesics but tolerance diminishes their efficacy.
  • Morphine activates ERK in tolerant rats, suggesting altered receptor signaling.
  • μ-opioid receptor (MOR) activation of ERK may involve dynamin-dependent endocytosis.

Purpose of the Study:

  • To test if MOR activation of ERK in the ventrolateral periaqueductal gray (vlPAG) depends on dynamin.
  • To investigate the role of dynamin in morphine tolerance and antinociception.

Main Methods:

  • Rats were rendered tolerant to morphine via vlPAG microinjections.
  • Dynamin's role was assessed using a dominant-negative dynamin peptide (Dyn-DN).
  • μ-opioid receptor internalization was monitored using a fluorescent dermorphin analogue (DERM-A594).

Main Results:

  • Morphine did not activate ERK in naïve rats; Dyn-DN had no effect.
  • In tolerant rats, Dyn-DN blocked morphine-induced ERK activation and inhibited antinociception.
  • Morphine reduced DERM-A594 internalization in tolerant rats, indicating receptor unavailability.

Conclusions:

  • Repeated morphine administration enhances MOR-ERK signaling through a dynamin-dependent pathway.
  • This suggests altered functional selectivity of the MOR complex, favoring G-protein over dynamin-dependent signaling.
  • Dynamin-mediated receptor internalization contributes to opioid tolerance.
Keywords:
ERKendocytosisfunctional selectivityligand biasmorphinemorphine toleranceopiateopioidperiaqueductal gray

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